The formation of medium and large rings is an important general process in synthetic organic chemistry, since a variety of natural products contain macrocyclic rings. This proposal describes a systematic theoretical study of the factors influencing macrocyclization reactions. During the last few years, we have begun to develop methods which allow the quantitative modeling of organic reactivity. These same techniques should facilitate a comprehensive study of the factors influencing the rates of formation of macrocycles. This project will develop the understanding both of the conformations of medium and large rings and of the transition states leading to them in common macrocyclization reaction. The study will involve the development and evaluation of methods to generate conformations of flexible molecules, and to minimize energies of multiple minima with accuracy and efficiency. Calculational studies will be applied to the factors controlling rates of cyclizations, and to develop methods to design favorable macrocyclization reactions and substrates. These generalizations will be developed as we study the following specific macrocyclization problems: (1) lactonizations and intramolecular SN2 reactions; (2) the relationships between stereochemistries and protecting groups and the rates of formation of macrolides such as erythronolides from acyclic precursors; (3) rates of intramolecular nucleophilic additions which form large rings; (4) intramolecular radical cyclizations to form medium and large rings.